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Conclusion: In this pilot study, early effective CA was associated with better neurological outcome in patients with IS. Dynamic CA may carry significant prognostic implications.

Introduction

Reperfusion and neuroprotection are the current mainstays of acute ischemic stroke (IS) management. In this regard, arterial blood pressure (ABP) management may play a central role to maintain optimal perfusion within the vulnerable ischemic penumbra (1, 2). Unfortunately, several clinical trials in ABP modulation had no effect on prognosis (2) and, therefore, the corresponding current guidelines remain evasive (3). Perhaps, the crucial factor is not ABP per se, but rather how cerebral blood flow can adapt to pressure changes and/or demand, i.e., cerebral autoregulation (CA) (4).

Dynamic CA (dCA) can be assessed using transfer function analysis (TFA) between spontaneous oscillations of ABP and cerebral blood flow velocity (CBFV) (4). CA has been studied in acute stroke (5) with conflicting results (5–8), but the early hours, where penumbra is more vulnerable, has been largely ignored.

Therefore, we aimed to assess dCA within 6 h of IS symptoms and its relationship with final infarct volume and 90-day functional outcome.

Discussion

We showed that the efficacy of dCA during the first 6 h after symptom onset is associated with smaller infarct volumes at 24 h and better neurological outcome at 3 months.

Transfer function analysis of the spontaneous ABP and CBFV oscillations is increasingly used to assess dCA in a number of neurovascular disorders (7–10). The phase of this relationship, which represents the time delay between these oscillating waveforms, has emerged as a significant predictor of outcome. Lower phase shift (ineffective CA) has been linked to carotids or MCA stenosis (11) or development of vasospasm after subarachnoid hemorrhage (10). In patients with IS, phase has also been linked to stroke severity (5, 7). The impaired CA can be also related to patient medical conditions not addressed in this study. For example, impaired cerebral autoregulation in patients with sleep apnea has been linked to an increased risk of stroke (12). Our findings, which build on these prior studies, show that effective dCA, as demonstrated by higher phase shift, is linked to smaller stroke volumes and better neurological outcome. Moreover, consistent with prior work where a phase >30 represents effective or intact autoregulation (4, 5, 9), we also found a cutoff value of 37° for phase that was predictive of neurological independence at 3 months and smaller stroke volumes at 24 h.

Interestingly, we also found that a lower systolic ABP is associated with larger infarcts but only if CA is impaired in the infarct side (phase <37°). This observation enhances the biological plausibility of the link between phase (dCA), stroke volume and clinical outcome, since lower ABP would only endanger the ischemic penumbra with further hypoperfusion if CA was impaired. Taken together, CA assessment could, therefore, identify patients who would benefit from BP augmentation in future clinical trials (13) Perfusion imaging, instead of CA assessment, may have been more helpful to explain larger infarcts at 24 h by estimation of initial penumbra area. However, an impaired CA at baseline could itself be responsible for this larger penumbra. The question remains to be answered in future studies with correlative measurements with perfusion scanning.

In line with prior studies (5), gain seems not to be a good marker for stroke outcome. Nevertheless, lower gain values (more effective CA) on the stroke side seemed to be associated with independence at 3 months.

This study has some limitations. As it is a pilot study, we enrolled a small number of subjects. Regarding the TCD method, there are limitations inherent to CA assessment with TCD (4), as some non-stationary conditions (e.g., agitation, mental changes) might turn linear methods like TFA less reliable. Also, M1 occlusions could not be assessed. As CA was assessed after IV thrombolysis within 6 h of symptoms, non-occluded M1 cases in this study include recanalyzed MCA or branch occlusions while those who were excluded due to M1 occlusion are mostly non-recanalized MCA. Having said that, we still can see this as a limitation but occluded M1 after IV thrombolysis is itself a maker for very bad prognosis and we believed that CA assessment would not add any significant contribution in this scenario; we also monitored this excluded cases and only 1/16 (6%) was independent at 3 months and all had total MCA area involvement. So, what our study points out is that even if we recanalyze the MCA artery <6h, those with better CA (phase ≥37°) will have higher chance of being independent at 3 months.

Concerning the infarct volume, we used CT scan, which is not as reliable as MRI. However, most of the stroke patients had easily identifiable partial or total areas of MCA infarct. Although CT scan is a coarse measure, we believe that the overall results were not influenced by this method.

1. In summary, we showed that the efficacy of dCA in the early hours of IS is linked to infarct volume at 24 h and neurological outcome at 3 months. Rapid bedside assessment of CA may help to identify a high risk population with impaired CA who would benefit from different BP management.

Ethics Statement

This study was carried out in accordance with the recommendations of São João Hospital center ethical committee with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the São João Hospital center ethical committee.

Author Contributions

PC reviewed the literature, designed the study, extracted the data, analyzed the results, and wrote the paper. EA designed the study, analyzed the results, and co-wrote the paper. IR and JS designed the study, analyzed the results, and reviewed the paper. FS reviewed the literature, designed the study, analyzed the results, and co-wrote the paper.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

This study was part of Ph.D. thesis of PC and received public national grant from Fundação para a Ciência e a Tecnologia (FCT), Portugal, PTDC/SAU-ORG/113329/2009. FS is supported by R01 NS085002 (NINDS).